Many studies have suggested a relationship between depression and cardiovascular disease (CVD), but its causal role in the etiology of CVD is still debated and the mechanisms are unclear. Rather than being causally related, depression and CVD could share common environmental risk factors, such as exposure to stressful events or unhealthy lifestyle, or a common genetic substrate. In the past funding period, we studied the cross-sectional relationship between depression and subclinical CVD in a genetically informative sample of monozygotic (MZ) and dizygotic (DZ) male twins. This sample included twin pairs discordant for lifetime history of major depression and a control sample of pairs without depression. Although this study, called Twins Heart Study (THS), has provided important new data, it remains limited by its cross-sectional design. In this two-year competing renewal grant, we propose to further clarify the role of depression on CVD using a prospective design in which we will study changes over time in CVD measures. We propose to re-examine 80 twin pairs discordant for major depressive disorder (MDD) from the initial THS population about 7 years after the initial assessment. Given that a comprehensive set of CVD measures and risk factors was obtained in the initial assessment, this continuation project offers a unique opportunity to examine CVD progression as a function of depression in a genetically informative sample. The aims of the study are: 1) to determine whether twins with depression, compared with their brothers without depression, show greater progression of CVD, including coronary flow reserve, measured by means of Positron Emission Tomography, carotid intima-media thickness, and forearm flow-mediated vasodilation, both measured with ultrasound;2) to investigate biological mechanisms underlying the potential association between depression and CVD progression, including neurohormonal/autonomic factors, inflammation and oxidative stress;3) to determine whether there are shared genetic or environmental pathways between depression and CVD. Clarification of these mechanisms will improve our understanding of the etiology of CVD and ultimately point to more effective prevention strategies for the identification and treatment of individuals at highest risk of CVD.